Project Summary Heart failure is a leading cause of hospitalization and death. Since 1995, there has been no significant decline in heart failure, reflecting the absence of new medical developments for its treatment. Therefore, developing new approaches to heart failure is a large, unmet need. One of the leading causes of congestive heart failure is cardiomyopathy, a disorder with a high heritable component. Genetic studies of familial cardiomyopathy have identified more than 70 different genes that, when mutated, cause cardiomyopathy and heart failure. An improved understanding of the genetic defects that underlie heart failure and cardiomyopathy provides prognostic information to guide clinical decision-making and to provide better information about the biological underpinnings of heart failure. Genetic diagnosis in cardiomyopathy may also help define subclasses of cardiomyopathy to better guide therapy. Importantly, genetic diagnosis affords the opportunity for early detection and early intervention. The current strategy for genetic diagnosis relies on gene panels, where multiple genes are sequenced simultaneously, and nearly all these genes encode proteins are known cardiac function including thick and thin filament proteins and those important for cytoskeletal and nuclear integrity. We propose to conduct comprehensive genome sequencing in cardiomyopathy patients to define the range of pathogenic variation present in subjects with cardiomyopathy. Initial analysis will focus on rare variants that affect the coding regions of genes, especially those that are predicted to disrupt protein production. To this end, noncoding regions will also be surveyed with emphasis on deletions or duplication (also known as structural variants) that disrupt regulatory regions for the genes known to be linked to cardiomyopathy as well as those that affect microRNAs and long noncoding RNAs. Data from individual cardiomyopathy genomes will be verified by family segregation studies. This database of genetic variation in cardiomyopathy will generate a publically available resource that will aid in interpretation of clinical genetic testing, identify new mutations in known genes as well as new genes important for cardiomyopathy.